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NEW FINDINGS What is the central question of this study? Does the muscle metaboreflex affect the ratio of left ventricular contraction/relaxation rates and does heart failure impact this relationship. What is the main finding and its importance? The effect of muscle metaboreflex activation on the ventricular relaxation rate was significantly attenuated in heart failure. Heart failure attenuates the exercise and muscle metaboreflex-induced changes in the contraction/relaxation ratio. In heart failure, the reduced ability to raise cardiac output during muscle metaboreflex activation may not solely be due to attenuation of ventricular contraction but also alterations in ventricular relaxation and diastolic function. ABSTRACT The relationship between contraction and relaxation rates of the left ventricle varies with exercise. In in vitro models, this ratio was shown to be relatively unaltered by changes in sarcomere length, frequency of stimulation, and β-adrenergic stimulation. We investigated whether the ratio of contraction to relaxation rate is maintained in the whole heart during exercise and muscle metaboreflex activation and whether heart failure alters these relationships. We observed that in healthy subjects the ratio of contraction to relaxation increases from rest to exercise as a result of a higher increase in contraction relative to relaxation. During muscle metaboreflex activation the ratio of contraction to relaxation is significantly reduced towards 1.0 due to a large increase in relaxation rate matching contraction rate. In heart failure, contraction and relaxation rates are significantly reduced, and increases during exercise are attenuated. A significant increase in the ratio was observed from rest to exercise although baseline ratio values were significantly reduced close to 1.0 when compared to healthy subjects. There was no significant change observed between exercise and muscle metaboreflex activation nor was the ratio during muscle metaboreflex activation significantly different between heart failure and control. We conclude that heart failure reduces the muscle metaboreflex gain and contraction and relaxation rates. Furthermore, we observed that the ratio of the contraction and relaxation rates during muscle metaboreflex activation is not significantly different between control and heart failure, but significant changes in the ratio in healthy subjects due to increased relaxation rate were abolished in heart failure.

Muscle metaboreflex activation (MMA) during submaximal dynamic exercise in normal individuals increases mean arterial pressure (MAP) via increases in cardiac output (CO) with little peripheral vasoconstriction. The rise in CO occurs primarily via increases in heart rate (HR) with maintained or slightly increased stroke volume. When the reflex is sustained during recovery (postexercise muscle ischemia, PEMI), HR declines yet MAP remains elevated. The role of CO in mediating the pressor response during PEMI is controversial. In seven chronically instrumented canines, steady-state values with MMA during mild exercise (3.2 km/h) were observed by reducing hindlimb blood flow by ∼60% for 3–5 min. MMA during exercise was followed by 60 s of PEMI. Control experiments consisted of normal exercise and recovery. MMA during exercise increased MAP, HR, and CO by 55.3 ± 4.9 mmHg, 42.5 ± 6.9 beats/min, and 2.5 ± 0.4 l/min, respectively. During sustained MMA via PEMI, MAP remained elevated and CO remained well above the normal recovery levels. Neither MMA during dynamic exercise nor during PEMI significantly affected peripheral vascular conductance. We conclude that the sustained increase in MAP during PEMI is driven by a sustained increase in CO not peripheral vasoconstriction.

Muscle metaboreflex activation (MMA) during dynamic exercise increases cardiac work and myocardial O2 demand via increases in heart rate, ventricular contractility, and afterload. This increase in cardiac work should lead to metabolic coronary vasodilation; however, no change in coronary vascular conductance occurs. This indicates that the MMA-induced increase in sympathetic activity to the heart, which raises heart rate, ventricular contractility, and cardiac output, also elicits coronary vasoconstriction. In heart failure, cardiac output does not increase with MMA presumably due to impaired ability to improve left ventricular contractility. In this setting actual coronary vasoconstriction is observed. We tested whether this coronary vasoconstriction could explain, in part, the reduced ability to increase cardiac performance during MMA. In conscious, chronically instrumented dogs before and after pacing-induced heart failure, MMA responses during mild exercise were observed before and after α1-adrenergic blockade (prazosin 20–50 μg/kg). During MMA, the increases in coronary vascular conductance, coronary blood flow, maximal rate of left ventricular pressure change, and cardiac output were significantly greater after α1-adrenergic blockade. We conclude that in subjects with heart failure, coronary vasoconstriction during MMA limits the ability to increase left ventricular contractility.

Ischemia of active skeletal muscle elicits a pressor response termed the muscle metaboreflex. We tested the hypothesis that in normal dogs during dynamic exercise, graded muscle metaboreflex activation (MMA) would progressively attenuate spontaneous heart rate baroreflex sensitivity (SBRS). The animals were chronically instrumented to measure heart rate (HR), cardiac output (CO), mean and systolic arterial pressure (MAP and SAP), and left ventricular systolic pressures (LVSP) at rest and during mild or moderate treadmill exercise before and during progressive MMA [via graded reductions of hindlimb blood flow (HLBF)]. SBRS [slopes of the linear relationships (LRs) between HR and LVSP or SAP during spontaneous sequences of ≥3 consecutive beats when HR changed inversely vs. pressure] decreased during mild exercise from the resting values (−5.56 ± 0.86 vs. −2.67 ± 0.50 beats·min−1·mmHg−1, P −1·mmHg−1, P

We have previously shown that spontaneous baroreflex-induced changes in heart rate (HR) do not always translate into changes in cardiac output (CO) at rest. We have also shown that heart failure (HF) decreases this linkage between changes in HR and CO. Whether dynamic exercise and muscle metaboreflex activation (via imposed reductions in hindlimb blood flow) further alter this translation in normal and HF conditions is unknown. We examined these questions using conscious, chronically instrumented dogs before and after pacing-induced HF during mild and moderate dynamic exercise with and without muscle metaboreflex activation. We measured left ventricular systolic pressure (LVSP), CO, and HR and analyzed the spontaneous HR-LVSP and CO-LVSP relationships. In normal animals, mild exercise significantly decreased HR-LVSP (−3.08 ± 0.5 vs. −5.14 ± 0.6 beats·min−1·mmHg−1; P < 0.05) and CO-LVSP (−134.74 ± 24.5 vs. −208.6 ± 22.2 ml·min−1·mmHg−1; P < 0.05). Moderate exercise further decreased both and, in addition, significantly reduced HR-CO translation (25.9 ± 2.8% vs. 52.3 ± 4.2%; P < 0.05). Muscle metaboreflex activation at both workloads decreased HR-LVSP, whereas it had no significant effect on CO-LVSP and the HR-CO translation. HF significantly decreased HR-LVSP, CO-LVSP, and the HR-CO translation in all situations. We conclude that spontaneous baroreflex HR responses do not always cause changes in CO during exercise. Moreover, muscle metaboreflex activation during mild and moderate dynamic exercise reduces this coupling. In addition, in HF the HR-CO translation also significantly decreases during both workloads and decreases even further with muscle metaboreflex activation.

Dynamic cardiac baroreflex responses are frequently investigated by analyzing the spontaneous reciprocal changes in arterial pressure and heart rate (HR). However, whether the spontaneous baroreflex-induced changes in HR translate into changes in cardiac output (CO) is unknown. In addition, this linkage between changes in HR and changes in CO may be different in subjects with heart failure (HF). We examined these questions using conscious dogs before and after pacing-induced HF. Spontaneous baroreflex sensitivity in the control of HR and CO was evaluated as the slopes of the linear relationships between HR or CO and left ventricular systolic pressure (LVSP) during spontaneous sequences of greater or equal to three consecutive beats when HR or CO changed inversely versus pressure. Furthermore, the translation of baroreflex HR responses into CO responses (HR-CO translation) was examined by computing the overlap between HR and CO sequences. In normal resting conditions, 44.0 ± 4.4% of HR sequences overlapped with CO sequences, suggesting that only around half of the baroreflex HR responses cause CO responses. In HF, HR-LVSP, CO-LVSP, and the HR-CO translation significantly decreased compared with the normal condition (−2.29 ± 0.5 vs. −5.78 ± 0.7 beats·min−1·mmHg−1; −70.95 ± 11.8 vs. −229.89 ± 29.6 ml·min−1·mmHg−1; and 19.66 ± 4.9 vs. 44.0 ± 4.4%, respectively). We conclude that spontaneous baroreflex HR responses do not always cause changes in CO. In addition, HF significantly decreases HR-LVSP, CO-LVSP, and HR-CO translation.

Sympathoactivation may be excessive during exercise in subjects with hypertension, leading to increased susceptibility to adverse cardiovascular events, including arrhythmias, infarction, stroke, and sudden cardiac death. The muscle metaboreflex is a powerful cardiovascular reflex capable of eliciting marked increases in sympathetic activity during exercise. We used conscious, chronically instrumented dogs trained to run on a motor-driven treadmill to investigate the effects of hypertension on the mechanisms of the muscle metaboreflex. Experiments were performed before and 30.9 ± 4.2 days after induction of hypertension, which was induced via partial, unilateral renal artery occlusion. After induction of hypertension, resting mean arterial pressure was significantly elevated from 98.2 ± 2.6 to 141.9 ± 7.4 mmHg. The hypertension was caused by elevated total peripheral resistance. Although cardiac output was not significantly different at rest or during exercise after induction of hypertension, the rise in cardiac output with muscle metaboreflex activation was significantly reduced in hypertension. Metaboreflex-induced increases in left ventricular function were also depressed. These attenuated cardiac responses caused a smaller metaboreflex-induced rise in mean arterial pressure. We conclude that the ability of the muscle metaboreflex to elicit increases in cardiac function is impaired in hypertension, which may contribute to exercise intolerance.

We tested whether mild and moderate dynamic exercise and muscle metaboreflex activation (MMA) affect dynamic baroreflex control of heart rate (HR) and cardiac output (CO), and the influence of stroke volume (SV) fluctuations on CO regulation in normal (N) and pacing-induced heart failure (HF) dogs by employing transfer function analyses of the relationships between spontaneous changes in left ventricular systolic pressure (LVSP) and HR, LVSP and CO, HR and CO, and SV and CO at low and high frequencies (Lo-F, 0.04–0.15 Hz; Hi-F, 0.15–0.6 Hz). In N dogs, both workloads significantly decreased the gains for LVSP-HR and LVSP-CO in Hi-F, whereas only moderate exercise also reduced the LVSP-CO gain in Lo-F. MMA during mild exercise further decreased the gains for LVSP-HR in both frequencies and for LVSP-CO in Lo-F. MMA during moderate exercise further reduced LVSP-HR gain in Lo-F. Coherence for HR-CO in Hi-F was decreased by exercise and MMA, whereas that in Lo-F was sustained at a high level (>0.8) in all settings. HF significantly decreased dynamic HR and CO regulation in all situations. In HF, the coherence for HR-CO in Lo-F decreased significantly in all settings; the coherence for SV-CO in Lo-F was significantly higher. We conclude that dynamic exercise and MMA reduces dynamic baroreflex control of HR and CO, and these are substantially impaired in HF. In N conditions, HR modulation plays a major role in CO regulation. In HF, influence of HR modulation wanes, and fluctuations of SV dominate in CO variations.

Muscle metaboreflex activation during dynamic exercise induces a substantial increase in cardiac work and oxygen demand via a significant increase in heart rate, ventricular contractility, and afterload. This increase in cardiac work should cause coronary metabolic vasodilation. However, little if any coronary vasodilation is observed due to concomitant sympathetically induced coronary vasoconstriction. The purpose of the present study is to determine whether the restraint of coronary vasodilation functionally limits increases in left ventricular contractility. Using chronically instrumented, conscious dogs ( n = 9), we measured mean arterial pressure, cardiac output, and circumflex blood flow and calculated coronary vascular conductance, maximal derivative of ventricular pressure (dp/d tmax), and preload recruitable stroke work (PRSW) at rest and during mild exercise (2 mph) before and during activation of the muscle metaboreflex. Experiments were repeated after systemic α1-adrenergic blockade (∼50 μg/kg prazosin). During prazosin administration, we observed significantly greater increases in coronary vascular conductance (0.64 ± 0.06 vs. 0.46 ± 0.03 ml·min−1·mmHg−1; P < 0.05), circumflex blood flow (77.9 ± 6.6 vs. 63.0 ± 4.5 ml/min; P < 0.05), cardiac output (7.38 ± 0.52 vs. 6.02 ± 0.42 l/min; P < 0.05), dP/d tmax(5,449 ± 339 vs. 3,888 ± 243 mmHg/s; P < 0.05), and PRSW (160.1 ± 10.3 vs. 183.8 ± 9.2 erg·103/ml; P < 0.05) with metaboreflex activation vs. those seen in control experiments. We conclude that the sympathetic restraint of coronary vasodilation functionally limits further reflex increases in left ventricular contractility.